Objective: To determine the effect of selective metabotropic glutamate type 2 (mGlu2) receptor positive allosteric modulation as monotherapy on parkinsonism, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset.
Background: We have previously found that mGlu2 positive allosteric modulation enhances the anti-parkinsonian action of a therapeutic dose of L-3,4-dihydroxyphenylalanine (L-DOPA). The cortico-striatal synapse is over-active in parkinsonism. mGlu2 receptors are encountered at this important synapse where, upon stimulation, they reduce glutamate release, suggesting that mGlu2 activation could, on its own, reduce the severity of parkinsonism. Here, we sought to address this question by administering the prototypical and highly selective mGlu2 positive allosteric modulator (PAM) LY-487,379 to MPTP-lesioned marmosets.
Method: Parkinsonism was induced in 6 common marmosets (Callithrix jacchus, 3 females and 3 males) by MPTP injection. Marmosets were then administered the following treatments, in a randomised order: vehicle/vehicle, L-DOPA/vehicle, vehicle/LY-487,379 1 mg/kg and vehicle/LY-487,379 10 mg/kg, after which the severity of parkinsonism was assessed by a blinded rater. The doses of LY-487,379 were selected from prior experiments we conducted in the marmoset.
Results: L-DOPA reduced global parkinsonian disability by 52% (P < 0.001). LY-487,379 1 mg/kg diminished global parkinsonism by 34% (P < 0.001), while LY-487,379 10 mg/kg lowered it by 48% (P < 0.001). Whereas the effect of L-DOPA had vanished after 3-4h, the effect of LY-487,379 was more sustained and a mild anti-parkinsonian effect was still manifest 5-6h after treatment administration.
Conclusion: Our results indicate that mGlu2 positive allosteric modulation may, as monotherapy, alleviate parkinsonism, suggesting a possible role for mGlu2 PAMs as DOPA-sparing agents in the treatment of early Parkinson’s disease.
To cite this abstract in AMA style:
I. Frouni, C. Kwan, S. Nuara, S. Belliveau, A. Hamadjida, W. Kang, D. Bédard, J. Gourdon, P. Huot. LY-487,379 alleviates parkinsonism when administered as monotherapy in the MPTP-lesioned marmoset [abstract]. Mov Disord. 2021; 36 (suppl 1). https://www.mdsabstracts.org/abstract/ly-487379-alleviates-parkinsonism-when-administered-as-monotherapy-in-the-mptp-lesioned-marmoset/. Accessed June 15, 2025.« Back to MDS Virtual Congress 2021
MDS Abstracts - https://www.mdsabstracts.org/abstract/ly-487379-alleviates-parkinsonism-when-administered-as-monotherapy-in-the-mptp-lesioned-marmoset/